Analgesic and antinociceptive methods

ABSTRACT

The present invention provides a method of attenuating the formation of a bruise and a method of attenuating swelling or inflammation in the tissue of a patient via applying a composition comprising a hydrophilic foam substrate and a polymeric hydrophilic agent capable of absorbing water to the surface of the skin.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional application of copending U.S. patent applicationSer. No. 09/326,836, filed Jun. 7, 1999, which claims priority to U.S.provisional patent application Ser. No. 60/088,424, filed Jun. 8, 1998.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to analgesic and antinociceptive methods.

BACKGROUND OF THE INVENTION

Peripheral nociceptors are neurons primarily responsible for respondingto noxious stimuli giving rise to pain. Most nociceptors arenon-myelinated C-fibers, and they are among the smallest diameter ofmammalian neurons (see, e.g., Chapter 48 in Textbook of MedicalPhysiology, 7^(th) Ed., Guyton, (W. B. Saunders, Co., 1986)). C-fibersare peptidergic neurons releasing tachykinins (notably Substance P andneurokinins), calcitonin gene-related peptide (CGRP), and otherneuroactive peptides. The peripheral nociceptor termini (the neuritesresponsible for initial transduction of noxious stimulus), liethroughout the body in cutaneous, subcutaneous and visceral organs andtissues (Dubner et al., Ann. Rev. Neurosci., 6, 381-418 (1983);Coggshall et al., Brain Res., 272, 185-88 (1983)). Generally, theperipheral termini of nociceptors are loosely arrayed into networks ofneurites able to interact with each other as well as react to endogenousand exogenous environmental noxious stimuli. Such networks represent thebranched termini of neurites lying within nerves whose somas are withinthe paired dorsal root ganglia (DRG) lying to each side of the spinalcolumn in a semisegmental array. Afferent nociceptor neurites run fromthe DRG to innervate the spinal substantia gelatinosa. Generally, spinalnociceptive innervation is via synapses with projection neuronsascending into the contralateral spinothalamic tract, through thethalamus, and ultimately to the cerebral cortex (Fields, 479-86 inAdvances in Pain Research and Therapy, Fields et al., eds. (Raven Press,New York, 1985); Jessell et al., 384-99 in Principles of Neural Science,3d. ed., Kandel et al., eds. (Elsevier, New York, 1991)).

Nociceptive neurons play a dual role in the transduction of noxiousstimuli. In one mode, nociceptors mediate local physiological responseto such stimuli. Roughly 90% of the substance P produced in nociceptorsomas is transported to the peripheral nociceptor termini (Levine etal., J. Immunol., 135, 843S-47S (1995); Brimjoin et al., Brain Res.,191, 443 (1986)). Upon stimulation, the peripheral nociceptor terminirelease peptide agents, which mediate a number of physiologicalresponses locally. Peripherally-released substance P and CGRP causevasodilation, increase vascular permeability, and trigger plasmaextravasation of cells in the region of the nerve termini (see, e.g.,Gamse et al., Eur. J. Pharmacol., 114, 61-66 (1985); Brain et al.,Nature, 313, 54-56 (1985); Reeh et al., Brain Res., 384, 42-50 (1980);Katz et al., Am. J. Med., 101, 1A55S-63S (1996)). Additionally,tachykinins effect degranulization of mast cells, which, in turn,release histamine. Thus, antidromic stimulation of nociceptors mediatesthe characteristic “wheal and flare” reaction, characterized by tissueswelling through the direct action of released substance P as well asindirectly, such as via increased local histamine concentration frommast cells (Katz, supra; Foreman et al., Agents and Actions, 13, 105-226(1983)). Within joints, such swelling is associated with arthritis(Levine et al., J. Immunol., 135, 843S-47S (1985); Levine et al.,Science, 226, 547-49 (1984)). Additionally, as mentioned, nociceptortermini are arranged in loose networks. Such networks effect cross-talkand interaction between nociceptor termini. Thus, stimulation ofnociceptors effects a positive feedback response on the nociceptorsthemselves, as substance P sensitizes nociceptors, and as histaminestimulates the nociceptors by reducing their threshold (Lembeck et al.,Trends Neurosci., 6, 106-08 (1983); Weihe, Ann. N.Y. Acad. Sci., 632,283-95 (1991)).

Aside from mediating local physiological change to noxious stimuli, thenociceptors transmit signals from the periphery to the central nervoussystem. The neural pathways primarily innervated by nociceptors areassociated with pain sensation. In this regard, the organization oftheir spinal innervation is important for the overall sensation of pain.Signals received by the aforementioned rising spinal neural pathwaysrepresent aggregation or summation of signals received from nociceptorsfrom a given level (or segment) of afferent inputs, whether thenociceptive nerve termini lie in the skin or internal organs. Thisorganization of afferent inputs generally produces a segmental map or“dermatome” representation of skin and internal organs relating tosegmental innervation, although some longitudinal cross-talk occurs. Dueto this aggregation, signals received from internal organs are often“felt” or experienced as if they originated in the same dermatome as theinternal organ (giving rise to phenomena such as “phantom pain” or“referred pain”). A similar arrangement exists for cranial nerves. Thus,there are relatively consistent dermatomal representations of internalorgans on the human body surface.

The neuroactive peptides (notably substance P) released by nociceptorsat the sites of their synapses in the central nervous system cansimultaneously stimulate other innervating nociceptive efferent terminiwithin the central nervous system. Due to antidromal signal conductancealong such nociceptors from the central nervous system, the peripheraltermini of nociceptors in areas distant from the situs of the noxiousstimuli can be caused to release tachykinins and other peptides. Thus,lateral cross-talk or reflexive input in the spinal column can lead to anociceptor mediated “neurogenic inflammation” in an area separate fromthe initial noxious stimulus (e.g., skin on the contralateral side,joints, internal organs, etc.) within the same dermatome (Levine et al.,J. Neurosci., 5, 1380-85 (1985)). Similarly, nociceptive input fromtermini lying in a given area of skin can often be “felt” or experiencedin a similar locus on the contralateral side of the animal, particularlywithin the same dermatome.

Considering their dual role in sensing pain and in effecting localresponses to nociceptive stimuli, several efforts have focused onblocking or attenuating nociceptor activity. One method of attenuatingnociceptor activity is via capsaicin, the active agent of red peppers.Capsaicin acts on C-fibers to deplete them of neuropeptides (Janscó etal., Naunyn-Schmiedberg Arch. Pharmacol., 313, 91-94 (1980)), leading todiminished response to noxious stimuli. Capsaicin can be appliedtopically, such as in a cream, to the skin, and it will diffuse throughthe skin to act on the subcutaneous C-fibers. Using capsaicin to blockC-fiber response poses several drawbacks. Notably, the compound cancause degeneration of the C-fibers (Janscó et al., Br. J. Pharmacol.,31, 138-51 (1967); Anton et al., Neurosci. Lett. Supp., 22, 31 (1985)).Moreover, capsaicin can irreversibly decrease the amount of substance Pin the skin (Gamse et al., Br. J. Pharmacol., 68, 207-13 (1980); Reeh etal., supra.). Some reports note that the compound must be appliedrepeatedly to be effective (Zochodne, et al., J. Can. Sci. Neurol., 20,69-72 (1993)). Also, many formulations for topical capsaicin applicationare incompatible with broken (e.g., wounded) skin. Furthermore, due toits mode of action by depleting the neuropeptides associated with pain,capsaicin application initially leads to acutely heightened painsensation and inflammation. This acute pain is experienced as anintolerable burning in some patients and renders controlled or blindstudies involving capsaicin difficult or impossible (Kost et al., NewEng. J. Med., 335, 32-42 (1996)).

Another means of affecting the nociceptors is with gold salts. Forexample, gold salts are effective against progressive joint destructionin patients with arthritis (Gottleib, 796-814 in Textbook ofRheumatology, Kelly et al., eds. (W. B. Saunders, Philadephia (1981)).Gold salts reduce swelling and pain through an irreversibleneurotoxicity specific for nociceptors (Levine et al., ArthritisRheumat., 29, 897-901 (1986)). Because gold salts destroy the C-fibers,employing them as therapeutic agents to minimize pain and swelling issuboptimal in many applications.

In view of the foregoing problems, there exists a need for a nontoxicmethod of attenuating the response of nociceptors to noxious stimuli andmitigating the symptoms thereof. The present invention seeks to overcomethese problems by providing a therapeutic method involving theapplication of a composition comprising a hydrophilic foam substrate, apolymeric hydrophilic agent capable of absorbing water, and a wettingagent to the surface of the skin. In various aspects and protocols, theinvention can promote healing and prevent the formation of a bruise intraumatized tissue, attenuate swelling and neurogenic inflammation,reduce the sensation of pain, and mitigate other symptoms associatedwith activation of the nociceptive system. These aspects of theinvention, as well as additional advantages and inventive features, willbe apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention concerns a method of treating a patient toattenuate, and in some cases eliminate, symptoms (e.g., pain,inflammation, bruising, etc.) normally caused or potentiated by theactivation of the nociceptive system through the use of a compositionincluding at least a hydrophilic foam substrate, a hydrophilic agentcapable of absorbing water, and a wetting agent to the surface of theskin. The composition is applied to the surface of the skin in an amountand at a location sufficient to attenuate the response of thenociceptors to noxious stimuli.

A preferred type of foam substrate for use in the inventive method is ahighly absorbent hydrophilic polyurethane foam composition, for example,the in situ reaction product of a reactant composition comprising anisocyanate-capped polyether prepolymer. Generally, such prepolymers mustbe safe for use in the human body, and are preferably capable of foamingin an aqueous system in the absence of a catalyst. On the other hand,such prepolymers should not dissolve in the aqueous liquid.Additionally, it is highly desirable that these prepolymers cure to forma porous cellular foam matrix to enable both absorption of externalfluids and carriage of the chosen wetting agent and hydrophylic agent inthe composition. The formation of a cellular foam matrix is preferreddue to a large volume available not only for absorption but thecontainment of the other constituents. It is further desirable that theprepolymers be capable of curing in the presence of water, in theabsence of catalyst, and at ambient temperature (e.g., about 20° C. toabout 30° C., preferably about 25° C.).

Isocyanate-capped polyether prepolymers, such as those disclosed in U.S.Pat. No. 3,903,232 and U.S. Pat. No. 4,137,200, are suitable for use ina hydrophilic polyurethane foam composition. These prepolymers have adefined average isocyanate functionality greater than 2. Theseprepolymers can be capped with aromatic isocyanates, such as, forexample, toluene diisocyanate or methylene diphenyl isocyanate, or withaliphatic isocyanates, such as isophorone diisocyanate.

Isocyanate-capped polyether prepolymers which have been found suitableinclude prepolymers sold under the trademark HYPOL. Examples includeHYPOL FHP 2000, HYPOL FHP 2002, HYPOL FHP 3000, HYPOL FHP 4000, HYPOLFHP 5000, HYPOL X6100 and HYPOL hydrogel. HYPOL 2000, HYPOL 2002 andHYPOL 3000 prepolymers are derived from toluene diisocyanate. FHP 2000and FHP 2002 both have an equivalent weight (per NCO) of 625, an NCOcontent of 1.60 meq/g and a specific gravity of 1.19. The viscosity ofFHP 2000 is 18,500 cps (Brookfield LVF, #4 Spindle, 12 rpm at 25° C.)and that of FHP 2002 is 20,000. FHP 3000 has an equivalent weight (perNCO) of 425, an NCO content of 2.35 meq/g, a specific gravity of 1.15and a viscosity (measured as described above) of 10,500. HYPOL hydrogelis likewise derived from toluene diisocyanate. It has an NCO content of0.5-0.9 meq/g and a viscosity of 10,000 to 12,000 cps at 25° C. TheHYPOL FHP 4000 and HYPOL FHP 5000 prepolymers are derived from methylenediisocyanate. FHP 4000 has an equivalent weight (per NCO) of 476, an NCOcontent of 2.10 meq/g, a Brookfield viscosity (LVF, #4 Spindle, 12r.p.m. at 25° C.) of 20,000 and specific gravity of 1.17. FHP 5000 hasan equivalent weight (per NCO) of 392, an NCO content of 2.55 meq/g, aBrookfield viscosity (measured as for FHP 4000) of 18,000 and a specificgravity of 1.17. HYPOL X6100 has an NCO content of 1.8 meq/grams and aviscosity at 25° C. of 12,000 cps.

Another example of an isocyanate-capped prepolymer suitable for use in ahydrophilic foam composition and derived from toluene diisocyanate isAQUAPOL prepolymer, commercially available from Freeman ChemicalCorporation. AQUAPOL prepolymers have an NCO-value of 2.5 to 3.0 and areformed from the reaction of toluene diisocyanate and an organicpolyether polyol containing at least 40 percent by weight ethylene oxideadducts as described at Col. 2, lines 3-22 of U.S. Pat. No. 4,517,326.

A further example of an isocyanate-capped prepolymer suitable for use ina hydrophilic foam composition and which is derived from toluenediisocyanate is sold under the trademark TREPOL, and is commerciallyavailable from Twin Rivers Engineering. TREPOL prepolymers have an ——NCOcontent of 1.4 meq per gram and a viscosity at 90° C. of 4,700 cps.

The amount of prepolymer in the reactant composition used to prepare thehydrophilic foam composition is not particularly critical, but dependson a number of factors, including the proportion of other components inthe reactant composition as will be described in greater detailhereinafter. However, there should be sufficient prepolymer to form apolyurethane foam, to adequately contain the hydrophilic agent andadjuvant (if present). To that end, the ratio of prepolymer tohydrophilic agent should be such that the reactant composition does notdegrade or break up into its separate constituents. Furthermore, whilethere should be sufficient prepolymer to provide integrity to the foammatrix, there should not be so much prepolymer that the resultingpolyurethane composition becomes unworkable. In short, and particularlywhere the final composition is to be applied to the skin, the resultingfoam composition is desirably relatively smooth and soft whileexhibiting the desired absorbence characteristics so that it does notirritate or otherwise harm the skin. The concentration of prepolymerfurther depends on its isocyanate functionality and the degree ofcrosslinking desired in the final foam composition. In general, thegreater the isocyanate functionality, the greater the degree ofcross-linking in the cured foam matrix. Typically, the reactantcomposition will comprise from about 20% to about 60% by weightprepolymer. Preferably the reactant composition will comprise from about45% to about 50% by weight of the prepolymer. Advantageously, theprepolymers can be used alone or in combination.

The composition further includes a hydrophilic agent, which isincorporated into the foam composition to absorb external liquid (e.g.,wound exudate, sweat, etc.) and to retain such liquid in thecomposition. The hydrophilic agent preferably is a highly absorbentpolymer, commonly known as a superabsorbent polymer. One measure ofpolymer absorbency is its fluid uptake capability, well known by thoseskilled in the art. Hydrophilic agents suitable for use in a hydrophilicfoam composition include polymers that are capable of absorbing at least50 times their weight of water, that is, such agents have a fluid uptakeof at least 50 ml/g. Hydrophilic agents having an even higher fluiduptake, such as of at least about 100 ml/g and even higher, that is, atleast about 150 ml/g are preferred. Suitable superabsorbent polymersinclude sodium and aluminum salts of starch grafted copolymers ofacrylates and acrylamides and combinations thereof, as well aspolyacrylate salts. Of course, other absorbent materials can be used incombination with such highly absorbent polymers, provided the fluiduptake of the overall combination used for the hydrophilic agent isgreater than 50 ml/g. Examples of such additives includemethylcellulose, guar gum, pectin, karaya gum, chitosan, agar, acaciapowder, carrageenan, gelatin and combinations thereof. When such agentsare employed, either alone or in combination, the resulting foamcomposition desirably has the ability to hold at least about 3 times itsweight in liquid.

Hydrophilic polymers which have been found suitable for use in the foamcomposition are commercially available from Grain ProcessingCorporation. These polymers include a starch-g-poly(2-propenamide-co-2-propenoic acid, mixed sodium and aluminum salt) soldunder the trademark WATER LOCK A-222; a starch-graft copolymer ofpolyacrylic acid and polyacrylamide having the chemical namestarch-g-poly (2-propenamide-co-2-propenoic acid, sodium salt), soldunder the trademark WATER LOCK A-100; a starch g-poly(2-propenamide-co-2-propenoic acid, sodium salt), sold under thetrademark WATER LOCK A-200. Superabsorbent polymers commerciallyavailable from Grain Processing Corporation under the trademark WATERLOCK D-212 and WATER LOCK D-242 are likewise suitable. These polymershave the chemical name starch-g-poly (2-propenamide-co-2-propenoic acid,mixed sodium and aluminum salt). The superabsorbent polymer commerciallyavailable under the trademark WATER LOCK G-400 is also suitable for usein the making of a hydrophilic foam composition. This superabsorbentpolymer can be chemically identified as a poly(2-propenamide-co-2-propenoic acid, sodium salt). Other super absorbentpowders suitable for use in a hydrophilic foam composition are sold byGrain Processing Corporation under the trademark WATER LOCK B, C, and H.

Another example of a suitable superabsorbent polymer is poly-2-propenoicacid, sodium salt, sold under the trademark AQUA KEEP J-500 supplied bySanyo Corp. In addition, super absorbent polymers sold by ArakawaChemical (USA) Inc. under the trademark ARASORB are suitable. Thepreferred hydrophilic polymers are WATER LOCK A-100, A-200, A-222 andAQUA KEEP J-500. The hydrophilic polymers can be used alone, or incombination to achieve the desired absorbance characteristics in thefoam composition.

The amount of hydrophilic agent used and the type of it, in terms of itsfluid uptake, that can be satisfactorily used to make the foamcomposition is not critical, but is, instead, dependent on the intendedapplication of the composition. The amount of hydrophilic agent shouldnot be so great as to undesirably reduce the strength of the foamcomposition or result in a loss of polymer from the foam, although someloss of hydrophilic agent can be tolerated without adversely affectingthe ability of the foam to absorb external liquid. The amount ofhydrophilic agent employed in the reactant composition will also dependon the absorbency of the material used. As previously indicated, it ispreferable that a sufficient amount of hydrophilic agent be employed sothat the resulting foam composition is capable of absorbing at leastabout 3 times its weight in external liquid. Typically this can beachieved by including from about 5 wt. % to about 20 wt. % hydrophilicagent in the reactant composition.

The wetting agent should not react with the foam composition or anycomponent of the foam formulation to create difficulties during foamformation or to adversely affect the desired characteristics of the foamcomposition in use or while being stored. Examples of materials that canbe used as the wetting agent, either alone or in admixture, includenonionic surfactants, such as block copolymers of ethylene oxide andpropylene oxide sold under the trademark PLURONIC by BASF Wyandottecorporation, ethoxylated sorbitan fatty acid esters, glycerol esters,polyglycerol esters, and silicone fluids. PLURONIC F-68 and L-62 arepreferred. As is known, PLURONIC F-68 aids in wound cleansing withoutcausing tissue damage. The use of PLURONIC F-68 is especially preferredbecause of its cleansing action, particularly because a portion of thesurfactant can be released when the foam composition is exposed to theexudate of the wound. Generally, the amount of wetting agent should befrom about 1% to about 10% by weight of the reactant composition,preferably from about 5% to about 7% by weight.

In addition to the hydrophilic foam substrate, polymeric hydrophilicagent capable of absorbing water, and wetting agent, the composition caninclude other ingredients. Indeed, preferably the composition includesat least one adjuvant, such as, for example, mono-, di- and polyhydricalcohols. Preferably such adjuvants are water soluble so that they aremiscible with biological fluids, especially those present in theextracellular matrix. It is also highly desirable that the adjuvant becapable of contacting skin without adverse side effects. To that end, itis also preferable that the adjuvant comprise a chemical compound thatwill have the ability to open the skin pores to achieve a demulcenteffect to relieve pain and/or irritation and to achieve an emollienteffect to soften the skin and prevent maceration. It is also preferredthat the adjuvant be compatible with therapeutic or other agents whichmay be carried by the composition (e.g., carried by the carrier, theadjuvant, or another component of the composition) for delivery to thesitus of application.

Suitable adjuvants include water-soluble alcohols, including monols,diols and polyhydric alcohols and other organic compounds with —OHgroups; and mixtures of such alcohols can likewise be used. In general,the molecular weight of the alcohols should be less than about 1000.Examples of monols include ethyl alcohol and isopropyl alcohol.Exemplary of suitable diols are propylene glycol, polyethylene glycoland polypropylene glycol. Exemplary of suitable polyhydric alcohols areglycerin, 1,2,4-butanetriol, trimethylolpropane, pentaerythritol andsorbitol. Glycerin is preferred as it has the attributes of amedicament, cosmetic or therapeutic agent.

Prior to curing, the adjuvant can serve as a plasticizer for thereactant foam composition. It extends the curing time of thecomposition, thereby allowing it to be more thoroughly mixed and formed.Once cured, the foam composition is softened by the adjuvant, allowingthe foam to be more pliable and more easily applied to the skin surfaceor other surface of choice. Additionally, the adjuvant can be somewhathygroscopic lending further to the hydrophilic nature of the foamcomposition. The amount of adjuvant included in the reactant compositionshould preferably be sufficient to impart softness and pliability to thefoam composition and be capable of delivering a therapeutic agent or thelike, if included, to the environment of application. However, thevolume of adjuvant should not be so great as to weaken or gel thecomposition. Generally, it has been found that the amount of adjuvant inthe reactant composition can be up to about 30 wt. % of the reactantcomposition.

Various additional medicaments, cosmetics and therapeutic agents can becarried within the composition and released to the desired situs. Thisrelease allows the transmission of such therapeutic or other agentscarried in the composition to the area of application outside thecomposition, further assisting in the beneficial treatment. Illustrativeof therapeutic agents which can be incorporated into the composition areCollasol 2400, Crotein SPA, Cromoist HYA, Crotein CAA and hydrocortisoneacetate and polymers with medicinal properties. Illustrative of cosmeticagents which can be incorporated into the composition are EuropeanCollagen Complex, Capture Complex Liposomes, Sardo™ bath oil, a handlotion sold under the trademark Jergens TM, Noxema™ skin cream, Oil ofOlay™ BF, Keri™ lotion, polymers with cosmetic properties, Vaseline™herbal and aloe lotion, Ben Gay™ ointment, Retin-A™ cream, andtrans-retinoic acid.

The composition for use in the inventive method can be prepared by anysuitable method, for example, as described in U.S. Pat. No. 5,254,301,incorporated herein by reference. Preferably, to effect foaming and thepreparation of the composition for use in the inventive method, suchmethod involves the preparation and mixing of an organic phase and anaqueous phase. The organic phase includes the prepolymer and preferablythe hydrophilic agent. The aqueous phase includes the wetting agent, thehydrophilic agent (if it is not included in the organic phase), andother desired additives, such as, for example, the adjuvant, dyes or thelike to color the resulting foam, medicaments, etc. To prepare the foam,the organic phase and aqueous phase are mixed at ambient temperature;the resulting mixture is then cast or extruded to form the foam. Thefoam can be prepared for subsequent use in a wound dressing or the likeby any suitable method. For example, a suitable substrate, such as aplastic (e.g. in the form of a sheet, laminate or fibrous mat), paper,foil, or the like can be provided and coated with a medically acceptableadhesive. Such adhesives are generally well known to those skilled inthe art. Then the reactant composition is poured directly onto theadhesive where the foam is formed. The foam can then be covered by acover sheet if desired. The resulting composite which comprises thesubstrate, adhesive, and foam can be die cut and later used itself, orit can be used as part of an occlusive or semi-occlusive wound dressing.

To assist in contacting the skin and effecting the nociceptive system asherein described, preferably, the surface of the foam which contacts theskin is not glassy or polished but somewhat rough in texture. Moreover,the foam preferably has a plurality of cells that vary in regard totheir average cell diameter. More preferably, cells of differingdiameter are distributed substantially randomly throughout thecomposition. For example, the cell size can range from about 0.002 mm toabout 3 mm, such as from about 0.01 mm to about 1 mm, and more typicallyfrom about 0.03 to about 0.06 mm. The foam composition will then assistin maintaining a moist seal appropriate to effectuate the inventivemethod. While many suitable compositions for use in the inventive methodcan be prepared as described above, a most preferred example of suchcomposition for use in the present inventive method is POLYMEM™,marketed by Ferris Manufacturing Corporation. Further examples ofsuitable compositions are disclosed in U.S. Pat. Nos. 5,064,563 and5,065,752, both of which are incorporated herein by reference.

For use in the inventive method, the composition is applied to anydesired area of the skin. The exact area of application will depend onthe desired result. Generally, the noxious response of nociceptorsinnervating the skin directly underlying the composition will beattenuated. Thus, for applications in which the noxious stimuli arelargely epidermal, the composition can be applied to the surface of theskin directly covering the afflicted area. In this regard, the degree towhich an individual neurite is affected by the presence of adjuvant isnot critical. As mentioned, the termini of nociceptors are looselyarranged in networks, and normal nociceptive response potentiates anentire local network through positive feedback (e.g., via sensitizationdue to substance P, stimulation via histamines, etc.). When the abilityof even a few nociceptor neurites to respond to noxious stimuli isattenuated, the capacity of an entire network within a discrete area torespond is dramatically reduced relative to its normal responsecapacity. Thus, the present inventive method effects an additiveresponse impacting the entire region of the skin underlying the site ofapplication.

Once affixed to the skin surface, a foam composition can adsorbmoisture, such as exudate moisture from a wound, sweat, etc. Inabsorbing the moisture, the foam swells to conform to the surfacecontour so as to become electrochemically insulative to the surface ofapplication, while at the same time holding moisture against the surfaceto keep that surface moist and to maximally permit the composition tocontact the skin while decreasing the exposure to air. Where the foamcomposition is used on an open wound, it does not adhere to the woundand thus does not cause reinjury upon its removal from the wound. Thisis believed to be due to the liquid exchange and the maintenance of amoist environment about the wound.

Without being bound by any particular theory, the hydrophilic agent isbelieved to work in conjunction with the foam matrix to hold moisture atthe surface of the skin. Thus, preferably the surface of skin to whichthe composition is applied is moist. This property facilitateselectrical conductance through a fluid continuum between the nociceptorneurons and the foam composition, in turn affecting the Donnanequilibrium across the membranes of nociceptive neurons, hyperpolarizingthem. Where the foam composition is applied to broken skin, thisproperty also allows healing agents exuded by the wound to beconcentrated and held at the wound surface. At the same time, thehydrophilic agent incorporated into the composition is believed toabsorb fluid from any wound to assist thickening of the blood, i.e., itserves as a hemostat. The absorption of exudate by the hydrophilicagent, and the subsequent swelling of the agent results in the removalof inflammatory exudates and particles that would otherwise hindertissue repair, cause scar formation, and stimulate nociceptors. Necroticdebris and bacteria are likewise removed as autolysis, i.e. chemicaldebridement is stimulated. Moreover, it is believed that the foam matrixserves as a capacitor to further effect the resting potential of theneurons. Thus, one aspect of the present invention involves altering thepolarization of peripheral nociceptors by applying the aforementionedcomposition to the surface of the skin. By such manipulation, theneurons are less able to conduct electrochemical signals. Hence theability of the nociceptors to respond to noxious stimuli, as well as toconduct both afferent and antidromal signals, is attenuated.

The effects of the present inventive method are not limited tointerfering with nociceptive responses in the skin adjacent to the areaon which the composition is applied. Indeed, the effects can be realizedat sites distant from the area of application, such as contralateralsites and internal sites. Thus, for example, applying the composition tothe skin surface can attenuate bruise formation deep to the surface(e.g., a bone bruise). For affecting nociceptors in joints (such as totreat arthritic or post operative swelling and/or pain), the compositionis applied to the surface of the skin overlying the joint. Moreover, asmentioned, nociceptive neural innervation of the central nervous systemeffects a dermatomic summation or experience of noxious stimuli,reflecting the quasi-segmental organization of peripheral inputs. Assuch, the inventive method can attenuate the response of central neuralpathways to nociceptive input from internal structures. Chiefly, byapplying the composition to the skin, the activity of the nociceptorsunderlying the composition is attenuated or minimized. As such, theinput received in the central nervous system lacks appreciable amount ofstimulus from the dermal afferents. Due to the dermatomal summationwithin the spinal column, this attenuation of dermal nociceptive inputis realized as an overall reduction in afferent input at the level of agiven dermatome. In some applications, this effect can reduce oreliminate pain stemming from noxious stimuli deep to the surface of theskin. For example, Table 1 indicates some dermal application sites foreffecting nociceptive input originating in various internal organs.Generally speaking, for interfering with dermatomic summation ofsignals, the area of skin within a given dermatome to which thecomposition is applied corresponds to the degree to which summationwithin the spinal column is affected. Thus, for a greater effect, moreskin should be covered with the composition.

TABLE 1 Nociceptor Terminal Origin Site of Application Upper mouth Skinover the maxillary division of the trigeminal nerve Lower mouth Skinover the mandibular division of the trigeminal nerve Lung andtracheo-bronchial Skin over the anterior and posterior tree cutaneousdivisions of spinal nerves C1 through T9 Stomach Skin over the anteriorand posterior divisions of spinal nerves T4 through T10 Esophagus Skinover the anterior and posterior divisions of spinal nerves C6 through T5Small intestines Skin over the anterior and posterior divisions ofspinal nerves T9 through T12 Large intestine/rectosigmoid Skin overanterior and posterior divisions of spinal nerves T12 through S3 Pelvicstructures Skin over the anterior and posterior divisions of spinalnerves T10 through S4 to their; skin over the pubic area anteriorly; theinner upper thigh area bilaterally and the sacral region posteriorly

As mentioned, nociceptive input to the central nervous system cansimultaneously stimulate other efferent termini within the centralnervous system, leading to neurogenic swelling and pain distant from thesitus of the initial noxious stimulus via antidromic conductance.Because the inventive method attenuates local nociceptor response tonoxious stimuli as well as their ability to conduct signals, the presentinventive method reduces or eliminates many neurogenic effects. Thus,application of the aforementioned compositions to the site of thenoxious stimulus reduces the effect on other areas (e.g., skin on thecontralateral side, joints, etc.). Furthermore, application of theaforementioned compositions to skin distant from the site of the noxiousstimulus reduces the response of skin underlying the composition toantidromic stimulation.

By thus attenuating nociceptive response, the inventive method mediatesseveral potentially therapeutic responses in the patient. The methodfunctions well in mammals, and is applicable to human and non-humanpatients (e.g., cats, dogs, horses, pigs, cattle, etc.). As mentioned,both through the direct action of neuropeptides and indirectly (e.g.,through the activities of cells responding to substance P), nociceptorsmediate bruise formation in response to trauma. Thus, by attenuating theresponse of nociceptors to such noxious stimuli, the inventive methodeffectively treats (i.e., promote the healing of) traumatized tissue ofa patient, for example, by attenuating the formation of bruises,inflammation, and swelling within such tissue. The method can be appliedto treat many types of trauma to tissue, e.g., resulting from surgicalor other therapeutic procedures, sports- or work-related injuries (forexample, sprains, inflammation, etc.), accidental injuries (such asresulting, from blows, burns, laceration, etc.), and other types oftrauma. In accordance with the inventive method, the composition can beapplied to the skin at any time following the trauma. However, thecomposition preferably is applied as soon as possible following thetrauma, to prevent and attenuate the tissue's response to the trauma.

Because, as mentioned, nociceptive neurons potentiate bruise formation,attenuating the response of nociceptors via the inventive methodinterferes with their ability to mediate bruise formation. Thus, in oneaspect, the invention pertains to a method of attenuating or preventingthe formation of a bruise in traumatized tissue involving theapplication of the aforementioned composition to the surface of theskin. Bruising can be attenuated in skin by applying the compositiondirectly to skin over the area subjected to trauma in an amount and at alocation sufficient to attenuate the formation of a bruise in thetraumatized tissue.

Because, as mentioned, nociceptors mediate neurogenic inflammatoryresponses in patients subjected to noxious stimuli, attenuating theresponse of nociceptors to such noxious stimuli interferes with theirability to mediate neurogenic inflammatory responses. Thus, a furtheraspect of the invention is a method of attenuating neurogenicinflammation in a patient involving the application of theaforementioned composition to the surface of the skin in an amount andat a location sufficient to attenuate neurogenic inflammatory responsein a patient. The method attenuates neurogenic inflammation regardlessof its cause. Thus, the method can reduce or prevent inflammation due tonoxious stimuli (e.g., burns, chemical irritants, pressure, wounding,etc.), allergies, or diseases (e.g., inflammatory diseases of the skin,such as acne, eczema, morphea, etc.). The method can attenuateneurogenic inflammation locally (e.g., by inhibiting the ability of agiven nociceptor to directly or indirectly affect surrounding tissues ora local array of peripheral nociceptor termini, as described herein).Alternatively, the method can attenuate neurogenic inflammation due toantidromic response of peripheral nociceptor termini by more centralstimulation (e.g., reflexive neurogenic responses, as described herein).The degree to which the method attenuates such neurogenic inflammationis sufficient to confer a therapeutic effect to the patient, and canrange from a slight reduction in redness or swelling to the completeblocking of such symptoms.

A further use of the inventive method is in treating swelling. Asmentioned, nociceptors mediate swelling in dermal and subdermal tissues.Thus, by attenuating the response of nociceptors, the present inventioninterferes with the ability of such neurons to stimulate each other andto release chemicals into the periphery which mediate swelling. As such,an aspect of the invention is a method of attenuating swelling in apatient via the application of the aforementioned composition to thesurface of the skin in an amount and at a location sufficient toattenuate swelling in the patient. The method can reduce extant swellingor prevent swelling from occurring. The method can reduce swellinglocally (e.g., in the skin underlying the area of compositionapplication). Alternatively, as mentioned, the method can attenuateswelling in tissues deep to the skin (e.g., within joints) within thesame dermatome of the area of skin to which the composition is applied.

A further use of the inventive method is in treating pain. As mentioned,in response to noxious stimuli, nociceptors transmit signals to centralnervous system neurons in neural pathways associated with painsensation. Thus, by attenuating the response of nociceptors to noxiousstimuli, the present invention interferes with the ability of suchneurons to inform the central nervous system of the noxious stimuli,thereby interfering with the neurophysiology as well as the sensation ofpain. In physiological terms, the application of the aforementionedcompositions to the surface of skin elevates the threshold ofstimulation required to effect the spinal pathways implicated in painsensation. As such, the inventive method elevates the threshold of pain.Viewed subjectively, the invention provides a method of reducing thesensation of pain in a patient via the application of the aforementionedcomposition to the surface of the skin in an amount and at a locationsufficient to attenuate the sensation of pain in the patient. The methodcan reduce pain locally (e.g., in the skin underlying the area ofcomposition application). Alternatively, as mentioned, the method canreduce pain in tissues deep to the skin within the same dermatome of thearea of skin to which the composition is applied.

The following examples further illustrate the invention. Of course, asthese examples are included for purely illustrative purposes, theyshould not be construed to limit the scope of the present invention inany respect.

EXAMPLE 1

This example demonstrates that the application of a compositioncomprising a hydrophilic foam substrate, a polymeric hydrophilic agentcapable of absorbing water, and a wetting agent to the surface of theskin prevents the formation of a bruise in traumatized tissue.

A patient was subjected to a blow to her upper arm. Immediatelythereafter, a patch consisting of POLYMEM™ was applied to the surface ofthe skin partially covering the traumatized area. Sixteen hours later,the arm was inspected, and it was observed that the skin surrounding thepatch had darkened, indicating that a bruise had formed. The compositionwas removed, and visual inspection surprisingly revealed nodiscoloration of the skin underlying the patch. In fact, the bruiseended in a sharply delineated line, representing the boundary of theskin over which the composition had been applied. The patient wasobserved 48 hours later, which revealed that, while the bruised area hadfaded normally, no bruise had developed in the area underlying thecomposition. These results demonstrate that the inventive methodprevents the formation of a bruise in traumatized tissue.

EXAMPLE 2

This example demonstrates that the application of a compositioncomprising a hydrophilic foam substrate, a polymeric hydrophilic agentcapable of absorbing water, and a wetting agent to the surface of theskin prevents the formation of a bruise in traumatized tissue.

A device was constructed to deliver calibrated blows consistently bydropping a weight of about 1.8 kg, falling a distance of 30 cm with acontact area of 1 cm². Fourteen New Zealand White rabbits (2.75-3.00 kg)were anesthetized and subjected to blows to the gastrocnemius area ofeach of hind leg using the device. Following the procedure, one hind legof each rabbit was immediately wrapped in a dressing consisting ofPOLYMEM™. To equalize pressure, the other leg was wrapped in a dressingconsisting of an ACE bandage.

After 24 hours, and again at 48 hours, the legs were uncovered andexamined. Bruises which had formed were graded between 1 (least severe)and 4 (most severe) by consensus of three researchers. The average valuefor the swelling in the POLYMEM™ treated legs 24 hours later wasdetermined to be 0.71, while the average in the control legs was 3.29.This difference was subjected to analysis by a Paired T-Test, and thedifference between the two average values was found to be very highlysignificant (p<0.001). The average swelling in the POLYMEM™ treated legs48 hours later was 0.29, while the average in the untreated legs was2.36. The T-Test determined that the difference between these twoaverages was very highly significant (p<0.001). These resultsdemonstrate that the inventive method prevents the formation of a bruisein traumatized tissue.

EXAMPLE 3

This example demonstrates that the application of a compositioncomprising a hydrophilic foam substrate, a polymeric hydrophilic agentcapable of absorbing water, and a wetting agent to the surface of theskin reduces the sensation of pain and attenuates swelling and bruising.

A 65-year-old male patient underwent arthroscopic surgery to remove ameniscus fragment from his right knee. After the surgery, the knee wasdressed with a dressing consisting of POLYMEM™.

Following this treatment, the patient required crutches on only oneoccasion the day of surgery to assist in mobility; the day following thesurgery, the patient was able to walk comfortably without orthotics. Thepatient did not experience significant post operative pain, and he wasnot given any pain medication.

The knee and surgical wound were examined on the day following surgery.The examination revealed only slight superficial swelling directlybeneath the sites of incision. The incision appeared neat anduncomplicated, and the skin evinced no sign of bruising.Musculoskelletal examination revealed 100% range of motion in the rightknee in flexion, extension, and rotation. Muscle tone was normal, andcomparison of the circumference of both legs revealed no loss of musclemass.

On the third day post-operation, the patient demonstrated completemobility without discomfort. He was able to conduct his normal dailyactivities without the need for pain medication or orthotic assistance.

The result of this procedure is surprising given the normal course ofrecuperation following such surgery in persons of similar age, whichusually requires substantial orthotic assistance and physical therapy.Indeed, the same individual underwent a similar operation about tenyears previously on his left knee. Following that procedure, heexperienced a prolonged healing process of about two months, includingphysical therapy.

EXAMPLE 4

This example demonstrates that the application of a compositioncomprising a hydrophilic foam substrate, a polymeric hydrophilic agentcapable of absorbing water, and a wetting agent to the surface of theskin reduces the sensation of pain.

24 individuals suffering from chronic lower back pain who had notresponded well to other therapies were identified. These individualswere treated for ten days by covering an area of their lower backs witha dressing consisting of POLYMEM™. After this ten day treatment, theindividuals were again examined, and 21 of them reported significantattenuation of their symptoms during the study.

EXAMPLE 5

This example demonstrates that the application of a compositioncomprising a hydrophilic foam substrate, a polymeric hydrophilic agentcapable of absorbing water, and a wetting agent to the surface of theskin attenuates neurogenic inflammation.

A young woman was diagnosed with morphea. Her symptoms included numerouslesions, characterized by areas of dry, nonviable skin, each surroundedby a border of raised, inflammatory tissue, spread across her back. Oneside of her back was covered with a dressing consisting of withPOLYMEM™, and the other side was left untreated. After this treatment,the inflammatory borders were absent and the pathologic process appearedto be quiescent. In contrast, the untreated side continued to exhibitthe characteristic lesions.

All of the references cited herein, including patents, patentapplications, and publications, are hereby incorporated in theirentireties by reference.

While this invention has been described with an emphasis upon preferredembodiments and illustrative and comparative examples, it will beobvious to those of ordinary skill in the art that variations of thepreferred embodiments may be used and that it is intended that theinvention may be practiced otherwise than as specifically describedherein. Accordingly, this invention includes all modificationsencompassed within the spirit and scope of the invention as defined bythe following claims.

What is claimed is:
 1. A method of attenuating the formation of a bruisein traumatized tissue of a patient, the method comprising applying acomposition applying a composition comprising a hydrophilic foamsubstrate and a polymeric hydrophilic agent capable of absorbing waterto a portion of the surface of the skin of the patient in an amount andat a location sufficient to attenuate the formation of a bruise in thethe traumatized tissue, wherein the totality of the portion is unbroken.2. The method of claim 1, wherein the tissue is traumatized as a resultof a surgical procedure.
 3. The method of claim 1, wherein the tissue istraumatized as a result of an injury.
 4. The method of claim 1, whereinthe tissue is muscle, bone, ligament, or skin.
 5. The method of claim 1,wherein the hydrophilic foam comprises the in situ reaction product of aisocyanate-capped polyether prepolymer.
 6. The method of claim 1,wherein the prepolymer is selected from the group consisting ofisocyanate-capped polyether polyols having an isocyanate equivalentweight of from about 0.5 meq/g to about 3.0 meq/g and mixtures thereof.7. The method of claim 1, wherein the hydrophilic agent is selected fromthe group consisting of starch grafted copolymers of acrylate salts,starch grafted copolymers of acrylamide salts, polyacrylate salts, andmixtures thereof.
 8. The method of claim 1, wherein the hydrophilicagent comprises an additive selected from the group consisting ofmethylcellulose, guar gum, pectin, karaya gum, chitosan, agar, acaciapowder, carrageenan, gelatin, and mixtures thereof.
 9. The method ofclaim 1, wherein the composition further comprises an alcohol selectedfrom the group consisting of water soluble monols, diols and polyhydricalcohols.
 10. The method of claim 1, wherein the composition furthercomprises an alcohol selected from the group consisting of ethanol,isopropyl alcohol, propylene glycol, polyethylene glycol, polypropyleneglycol, glycerin, 1, 2, 4-butanetriol, trimethylolpropane, sorbitol,pentaerythritol, and mixtures thereof.
 11. The method of claim 1,wherein the composition further comprises a therapeutic agent.
 12. Themethod of claim 11, wherein the therapeutic agent is selected from thegroup consisting of soluble collagen, hydrolyzed collagen, collagenamino acids salt free, hydrolyzed animal protein and hyaluronic acid, anointment including methyl salicylate and menthol and hydrocortisoneacetate, polymers with medicinal properties, and trans-retinoic acid.13. The method of claim 1, wherein the hydrophilic agent is incorporatedinto the foam substrate.
 14. The method of claim which further comprisesa wetting agent.
 15. The method of claim 14, wherein the wetting agentis a non-ionic surfactant selected from the group consisting of blockcopolymers of ethylene oxide and propylene oxide, ethoxylated sorbitanfatty acid esters, glycerol esters, polyglycerol esters, silicone fluidsand mixtures thereof.
 16. The method of claim 1, wherein the patient isa human.